Abstract:Monoclonal antibodies (mAbs) blocking immune checkpoint molecules, especially programmed cell death 1 (PD-1) and its ligands programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2), are currently been investigated for treatment of various tumors [1-3]. PD-L1 and PD-L2 are usually upregulated on the surface of multiple tumor cells to mediate immune tolerance through the interaction with inhibitory PD-1 molecule [4]. Thus, blocking PD-1/PD-Ls interaction has brought promising future for tumor immunotherapy… Show more
“…This is consistent with the general observation that the LCDR2 of antibodies is often not involved in antigen binding. The previously reported structures of PD-L1 in complex with BMS-963559 or avelumab demonstrated that these two antibodies similary involved only five of the six CDRs in the interaction with PD-L1, leaving LCDR2 without any binding to PD-L1 38, 39 .Figure 1Crystal structures of PD-1 in complex with atezolizumab and durvalumab. ( a ) Ribbon representation of the complex structure of PD-L1/atezolizumab Fab fragment.…”
Section: Resultsmentioning
confidence: 95%
“…5) 34, 37–39 .Figure 5Comparison of the PD-L1 interactions with the receptor PD-1 and anti-PD-L1 antibodies. ( a ) Structure of PD-L1 (pale blue) in complex with PD-1 (orange) and the PD-1 binding site (orange) on the surface of the IgSF V-set domain of PD-L1.…”
Section: Resultsmentioning
confidence: 99%
“…Recently, the crystal structures of PD-L1 in complex with the Fab fragment of BMS-936559 and the single-chain Fv fragment (scFv) of avelumab have been determined, revealing details of the antigen-antibody interactions 38, 39 . However, the epitopes and the PD-L1 blocking mechanism of atezolizumab and durvalumab remain unclear.…”
In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.
“…This is consistent with the general observation that the LCDR2 of antibodies is often not involved in antigen binding. The previously reported structures of PD-L1 in complex with BMS-963559 or avelumab demonstrated that these two antibodies similary involved only five of the six CDRs in the interaction with PD-L1, leaving LCDR2 without any binding to PD-L1 38, 39 .Figure 1Crystal structures of PD-1 in complex with atezolizumab and durvalumab. ( a ) Ribbon representation of the complex structure of PD-L1/atezolizumab Fab fragment.…”
Section: Resultsmentioning
confidence: 95%
“…5) 34, 37–39 .Figure 5Comparison of the PD-L1 interactions with the receptor PD-1 and anti-PD-L1 antibodies. ( a ) Structure of PD-L1 (pale blue) in complex with PD-1 (orange) and the PD-1 binding site (orange) on the surface of the IgSF V-set domain of PD-L1.…”
Section: Resultsmentioning
confidence: 99%
“…Recently, the crystal structures of PD-L1 in complex with the Fab fragment of BMS-936559 and the single-chain Fv fragment (scFv) of avelumab have been determined, revealing details of the antigen-antibody interactions 38, 39 . However, the epitopes and the PD-L1 blocking mechanism of atezolizumab and durvalumab remain unclear.…”
In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.
“…Crystal structures of the anti-PD-1 pembrolizumab Fab fragment complexed with hPD-1 and the anti-PD-L1 avelumab single chain Fv fragment (scFv) complexed with hPD-L1 have been determined by Na et al (2016) and our group, revealing the molecular basis of therapeutic antibody-based immune checkpoint therapy for tumors (Liu et al, 2016; Na et al, 2016). The interaction of pembrolizumab with hPD-1 is mainly located on two regions: the flexible C’D loop and the C, C’ strands.…”
Section: Structural Basis Of Therapeutic Antibody Interventionmentioning
confidence: 99%
“…Structural analysis of the interaction of avelumab with hPD-1 reveals that avelumab utilizes both V H and V L to bind to the IgV domain of PD-L1 on its side (Liu et al, 2016). The V H of avelumab dominates the binding to hPD-L1 by all three complementarity determining regions (CDR) loops, while V L contributes partial contacts by the CDR1 and CDR3 loops, leaving V L CDR2 without any binding to hPD-L1 (Fig.…”
Section: Structural Basis Of Therapeutic Antibody Interventionmentioning
Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.
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